chr16-68823560-C-A

Position:

• chr16-68823560-C-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004360.5(CDH1):​c.2098C>A​(p.Pro700Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,613,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: -1.80

Genes affected

CDH1 (HGNC:1748): (cadherin 1) This gene encodes a classical cadherin of the cadherin superfamily. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the mature glycoprotein. This calcium-dependent cell-cell adhesion protein is comprised of five extracellular cadherin repeats, a transmembrane region and a highly conserved cytoplasmic tail. Mutations in this gene are correlated with gastric, breast, colorectal, thyroid and ovarian cancer. Loss of function of this gene is thought to contribute to cancer progression by increasing proliferation, invasion, and/or metastasis. The ectodomain of this protein mediates bacterial adhesion to mammalian cells and the cytoplasmic domain is required for internalization. This gene is present in a gene cluster with other members of the cadherin family on chromosome 16. [provided by RefSeq, Nov 2015]

CDH1 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.084797025).
• BS2: High AC in GnomAdExome4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH1	NM_004360.5	c.2098C>A	p.Pro700Thr	missense_variant	13/16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.1915C>A	p.Pro639Thr	missense_variant	12/15		NP_001304113.1
CDH1	NM_001317185.2	c.550C>A	p.Pro184Thr	missense_variant	13/16		NP_001304114.1
CDH1	NM_001317186.2	c.133C>A	p.Pro45Thr	missense_variant	12/15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.2098C>A	p.Pro700Thr	missense_variant	13/16	1	NM_004360.5	ENSP00000261769.4

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152132 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461700 Hom.: 0 Cov.: 34 AF XY: 0.00000963 AC XY: 7 AN XY: 727142

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152132 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74308

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 21, 2020	DNA sequence analysis of the CDH1 gene demonstrated a sequence change, c.2098C>A, in exon 13 that results in an amino acid change, p.Pro700Thr. This sequence change does not appear to have been previously described in patients with CDH1-related disorders and has been described in the gnomAD database in one individual with an overall population frequency of 0.003% (dbSNP rs878854681). The p.Pro700Thr change affects a poorly conserved amino acid residue located in a domain of the CDH1 protein that is known to be functional. The p.Pro700Thr substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Pro700Thr change remains unknown at this time. -

Hereditary diffuse gastric adenocarcinoma Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto	Aug 01, 2022	Not applicable criteria (PMID: 30311375) -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 700 of the CDH1 protein (p.Pro700Thr). This variant is present in population databases (no rsID available, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 406634). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 17, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	May 01, 2023	The p.P700T variant (also known as c.2098C>A), located in coding exon 13 of the CDH1 gene, results from a C to A substitution at nucleotide position 2098. The proline at codon 700 is replaced by threonine, an amino acid with highly similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 27, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 15235021, 22850631) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.012
DANN	Benign	0.52
DEOGEN2	Benign	0.31	T;T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.28	T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.085	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L;.;.
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.71	N;.;N
REVEL	Benign	0.12
Sift	Benign	0.42	T;.;T
Sift4G	Benign	0.41	T;T;T
Polyphen		0.0010	B;.;.
Vest4		0.11
MutPred		0.48		Loss of ubiquitination at K697 (P = 0.0777);.;.;
MVP		0.53
MPC		0.28
ClinPred		0.15	T
GERP RS		-12
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.038
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs878854681; hg19: chr16-68857463;